Antiarrhythmic drugs are commonly divided into four classes according to their electro-physiological mode of action (Edvardsson, Current Therapeutic Research, Vol. 28, No. 1 Supplement, pages 113S-118S (July 1980); Keefe et al, Drugs, Vol. 22, pages 363-400 (1981); Vaughn-Williams, “Classification of Anti-Arrhythmic Drugs in Symposium of Cardiac Arrhythmias”, pages 449-472 (Sandoe et al, (eds.) A. B. Astra, Soederlaije, Sweden (1970)). Antiarrhythmic drugs are classified as follows: Class I—local anesthetic effect; Class II—beta-receptor blockade; Class III—prolongation of action potential duration; and Class IV—calcium antagonist.
Although it is generally considered a Class III antiarrhythmic drug, amiodarone possesses electrophysiologic characteristics of all four Vaughn-Williams classes: it blocks sodium channels at rapid pacing frequencies (Class I); it exerts a noncompetitive antisympathetic action (Class II); it prolongs the duration of the cardiac action potential (Class III); and it exhibits negative chronotropic effects on nodal tissues. Amiodarone possesses sustained efficacy against ventricular and supraventricular tachycardiarrhythmias. Amiodarone also exhibits vasodilatory action, which can decrease cardiac workload and consequently decrease myocardial oxygen consumption, and thus can be used to treat hypertension.
Amiodarone is approved for the treatment of life-threatening ventricular tachyarrhythmias. Amiodarone is also useful in treating less severe ventricular arrhythmias and many supraventricular arrhythmias including atrial fibrillation and reentrant tachyarrhythmias involving accessory pathways. Because amiodarone exhibits marked interindividual variations in response, close monitoring of the individual is essential to adjust the amount of the drug delivered. The most important treatment-emergent adverse effects are hypotension, asystole/cardiac arrest/electromechanical dissociation (EMD), cardiogenic shock, congestive heart failure, bradycardia, liver function abnormalities, VT, and AV block (Wyeth-Ayerst product insert CORDARONE® Intravenous).
Amiodarone reportedly exhibits complex disposition characteristics after the intravenous administration of a single therapeutic dose. Peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L. Peak serum concentrations after 10-minute infusions of 150 mg of CORDARON® I.V. in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% peak values within 30 to 45 minutes after the end of the infusion.
Amiodarone HCl ((2-butyl-3-benzofuranyl)[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone hydrochloride; C25H29I2NO3.HCl) is a white to slightly yellow crystalline powder, and is very slightly soluble in water (0.2-0.5 mg/ml). There are several reported pKa values for amiodarone: 5.6 (Andreasen et al., 1981), 7.4 (Canada et al., 1981), and 6.56 (Bonati et al., 1984). Amiodarone carries a positive charge at pH values below its pKa. Amiodarone HCl has the following chemical structure: 
The solubility of amiodarone hydrochloride in water is reportedly highly temperature dependent. The solubility ranges from 0.3 to 0.5 mg/ml at 20° C. to about 7 mg/ml at 50° C. At about 60° C., the solubility increases to greater than 100 mg/ml. At concentrations of about 50 mg/ml, amiodarone reportedly forms colloidal structures about 100 nm in diameter and micelles containing approximately 150 monomeric units and having a molecular weight in excess of 100,000.
Due to its low intrinsic water solubility, amiodarone is difficult to formulate in a water-based parenteral formulation that is sufficiently concentrated and stable and present in a medium having a physiologically acceptable pH. The currently marketed formulation (CORDARONE® Intravenous; CORDARONE I.V.®) of amiodarone contains 50 mg/ml amiodarone HCl, 20.2 mg/mL benzyl alcohol and 100 mg/mL polysorbate 80 (TWEEN® 80; a nonionic surfactant, emulsifier, dispersant and/or stabilizer) in water. The CORDARONE I.V.® formulation is packaged in single use containers.
Polysorbate 80 and benzyl alcohol, however, are known to cause unwanted side effects. For example, polysorbate 80, either alone or in combination with benzyl alcohol, reportedly acts as a potent cardiac depressant and causes hypotension, cancer. Moreover, parenteral administration of benzyl alcohol has reportedly been associated with hemolysis, death and a number of other side effects.
Aside from unwanted side effects, additional problems are associated with parenteral administration of a drug in a surfactant-based vehicle. For example, when the drug is diluted in the bloodstream two physical changes occur: 1) the pH and tonicity of the formulation approaches that of the blood; and 2) the concentrations of surfactant and drug are decreased proportionally to each other. In both instances the original composition of the formulation is altered, and a physically unstable solution may result. Specifically, if the drug in this diluted composition is present at a concentration which is greater than its solubility, a supersaturated solution with the potential to precipitate is formed (Ward, G. H and S. H. Yalkowsky in J. Parenter Sci. Technol. Vol. 47; 4:161-5 (1993)).
A number of patents and scientific publications disclose parenteral preparations of amiodarone that reportedly have reduced side effects as compared to the currently marketed formulation. U.S. Pat. No. 5,234,949 to Ehrenpreis et al. discloses a parenteral solution of amiodarone (25-75 mg/ml) in a surfactant-free acetate buffer solution having a pH below 4 and more preferably within the range of 3.5-3.8. Ehrenpreis et al. disclose that the concentration and choice of the buffering agent are critical for physical stability in order to reduce precipitation or gel formation. Solutions containing amiodarone at concentrations of 15-50 mg/ml in an acetate buffer with a pH of between 3.2 and 3.8 cannot be diluted in glucose-saline water beyond 1 mg/ml without forming very opalescent or even milky solutions.
U.S. Pat. No. 6,143,778 to Gautier et al. discloses a parenteral formulation containing amiodarone, a buffer solution and a non-ionic hydrophilic surfactant. The hydrophilic surfactant is required in order avoid the above-mentioned problem associated with dilution of a buffered solution containing amiodarone hydrochloride. Solutions containing 1.5-8.0% wt. amiodarone were reportedly prepared in the presence of surfactant. Solutions containing 30-50 mg amiodarone/mL of solution at pH 2.4-3.8 were reportedly prepared in the presence of buffers such as acetate (0.1-0.3 M), phosphate (0.1-0.15 M), or glycine (0.2 M), where the ionic strength was maintained between 0.08-0.3 M. At higher ionic strengths, cloudy solutions were reported. Citrate reportedly was not suitable at any concentration. Suitable surfactants reportedly included nonionic hydrophilic compounds with HLB values in the range of 13-29, and present in concentrations of about 0.5-2.0%. Some stated examples were Pluronics®, Cremophors®, Tweens® and Solutols®. The formulation reportedly could be diluted to concentrations both approximating (˜0.5-0.8 mg/mL) and below (0.1-0.15 mg/mL) the amiodarone micellar concentration.
Ravin et al. (J. Pharm. Sci. (1975), 64(11), 1830-1833) disclose that chloride ion suppresses the solubility of amiodarone and that sodium citrate and tartrate, in very low concentrations ranging from 0.002-0.008 M and at pH values of 4.3-5.4, increase the solubility of amiodarone to 4.8 and 6 mg/mL, respectively. At higher concentrations, however, the solubility was supressed. Under the conditions tested, acetate in any concentration decreased the solubility of amiodarone at pH 4-4.7. The ability to prepare more concentrated solutions of amiodarone was demonstrated to be temperature dependent. At 25° C., 40° C., and about 60° C., amiodarone concentrations of 0.35 mg/mL, 0.95 mg/mL and >13 mg/mL, respectively, could be achieved. The solution heated to 60° C. could be cooled to 25° C. without precipitation; however, it could not be diluted to below the critical micellar concentration without precipitation.
Ravin et al. (J. Pharm. Sci. (1969), 58(10), 1242-45) report that cetyldimethyl-benzylammonium chloride, sodium lauryl sulfate and tween 80 increased the solubility of amiodarone at surfactant concentrations up to 0.02% wt.
Cyclodextrins and their derivatives are widely used in liquid formulations to enhance the aqueous solubility of hydrophobic compounds. Cyclodextrins are cyclic carbohydrates derived from starch. The unmodified cyclodextrins differ by the number of glucopyranose units joined together in the cylindrical structure. The parent cyclodextrins contain 6, 7, or 8 glucopyranose units and are referred to as α-, β-, and γ-cyclodextrin respectively. Each cyclodextrin subunit has secondary hydroxyl groups at the 2 and 3-positions and a primary hydroxyl group at the 6-position. The cyclodextrins may be pictured as hollow truncated cones with hydrophilic exterior surfaces and hydrophobic interior cavities. In aqueous solutions, these hydrophobic cavities provide a haven for hydrophobic organic compounds, which can fit all, or part of their structure into these cavities. This process, known as inclusion complexation, may result in increased apparent aqueous solubility and stability for the complexed drug. The complex is stabilized by hydrophobic interactions and does not involve the formation of any covalent bonds.
Chemical modification of the parent cyclodextrins (usually at the hydroxyl moieties) has resulted in derivatives with sometimes improved safety while retaining or improving the complexation ability of the cyclodextrin. Of the numerous derivatized cyclodextrins prepared to date, only two appear to be commercially viable; the 2-hydroxypropyl derivatives (HP-β-CD or HPCD), neutral molecules being commercially developed by Jannsen and others, and the sulfoalkyl ether derivatives (SAE-β-CD or SAE-CD), being developed by CyDex, Inc.
The SAE-CDs are a class of negatively charged cyclodextrins, which vary in the nature of the alkyl spacer, the salt form, the degree of substitution and the starting parent cyclodextrin. The sodium salt of the sulfobutyl ether derivative of beta-cyclodextrin, with an average of about 7 substituents per cyclodextrin molecule (SBE7-β-CD), is being commercialized by CyDex, Inc. (Kansas) as CAPTISOL® cyclodextrin. 
The anionic sulfobutyl ether substituent dramatically improves the aqueous solubility of the parent cyclodextrin. Reversible, non-covalent, complexation of drugs with the CAPTISOL® cyclodextrin generally allows for increased solubility and stability of drugs in aqueous solutions.
It has been reported that the relative increase in the solubility of a poorly soluble drug in the presence of an SAE-CD is a product of the binding constant and the molar concentration of SAE-CD present (Stella et al. in U.S. Pat. Nos. 6,046,177 and 5,874,418). Compounds usually exhibit a conventional type AL (‘A’ Linear) binding curve (Higuchi, T. and Connors, K. A. in “Advances in Analytical Chemistry and Instrumentation Vol. 4” (Reilly, Charles N. Ed., John Wiley & Sons., 1965, pp. 117-212)) when binding to an SAE-CD. In a typical type AL profile, the total solubility of the drug (y-axis) in water increases linearly with increasing concentrations of cyclodextrin present (x-axis). The data usually fits a straight line and rarely deviates from this relationship unless the particular compound (drug) being solubilized possesses an unexpected binding relationship with the SAE-CD. The y-intercept of a best-fit line through the data is equal to the theoretical intrinsic solubility of the drug in water.
Equations 1 and 2 generally describe the dynamic and reversible binding equilibrium, where the amount of drug, for example, in the complexed form is a function of the concentrations of the drug and cyclodextrin, and the equilibrium or binding constant, K1:1.Drug+Cyclodextrin←K1:1→Complex  Equation 1                              K                      1            :            1                          =                              [            Complex            ]                                              [              Drug              ]                        ⁡                          [              Cyclodextrin              ]                                                          Equation        ⁢                                   ⁢        2            
CAPTISOL® cyclodextrin is relatively new and its combined use with amiodarone for parenteral administration has not been evaluated.
U.S. Pat. No. 6,267,985 to Chen et al. discloses a method for improving the solubilization of triglycerides and improved delivery of therapeutic agents. The disclosed formulations comprise a combination of two surfactants, a triglyceride and therapeutic agent that is capable of being solubilized in the triglyceride, the carrier, or both the triglyceride and the carrier. The '985 Patent suggests the use of amiodarone and of an optional solubilizing agent, such as a cyclodextrin, which can include cyclodextrin derivatives such as hydroxypropyl cyclodextrin (HPCD), sulfobutyl ether cyclodextrin and a conjugate of sulfobutyl ether cyclodextrin. HPCD is the preferred cyclodextrin.
U.S. Pat. No. 6,294,192 to Patel et al. discloses triglyceride-free oral pharmaceutical compositions capable of solubilizing therapeutically effective amounts of hydrophobic therapeutic agents. The disclosed formulations include a combination of a hydrophilic surfactant and a hydrophobic surfactant. The '192 Patent suggests the use of amiodarone and of an optional solubilizing agent, such as a cyclodextrin, which can include cyclodextrin derivatives such as HPCD and sulfobutyl ether cyclodextrin. HPCD is the preferred cyclodextrin.
U.S. patent application Ser. No. 20020012680 to Patel et al. discloses triglyceride-free pharmaceutical compositions comprising a hydrophobic therapeutic agent, and a carrier comprising at least one hydrophilic surfactant and at least one hydrophobic surfactant. The application claims but does not teach the use of amiodarone as a suitable hydrophobic therapeutic agent. The claimed formulation can further comprise a solubilizer, which may be a sulfobutyl ether cyclodextrin.
U.S. Pat. Nos. 5,874,418 and 6,046,177 to Stella et al. disclose sulfoalkyl ether cyclodextrin-containing solid pharmaceutical compositions and formulations, and methods for their preparation for the sustained, delayed or controlled delivery of therapeutic agents. The patents disclose formulations containing a physical mixture of a sulfoalkyl ether cyclodextrin and a therapeutic agent, and optionally at least one release rate modifier. Both patents teach that the relative increase in the solubility of a poorly soluble drug in the presence of sulfoalkyl ether cyclodextrins (SAE-CDs) is a product of the binding constant and the molar concentration of SAE-CD present. In other words, Stella et al. disclose that the binding of an SBE-CD to a drug is governed by the formula set forth above. Amiodarone is listed as one of a large number of drugs that can be used.
U.S. Pat. Nos. 5,134,127 and 5,376,645 to Stella et al. disclose parenteral formulations containing an SAE-CD and a drug. Amiodarone is not included in the list of drugs that can be used.
International Publication No. WO 91/13100 to Coates et al. discloses liquid formulations containing amiodarone and 6A-amino-6A-deoxy-N-(3-carboxypropyl)-β-cyclodextrin (β-CDNSc) for IV injection. In an in vivo dog study, subjects were intravenously administered solutions containing 5 mg/kg amiodarone with or without β-CDNSc. AUC (0-24) and Cmax were increased following administration of the cyclodextrin-containing formulation, while no significant changes were found in the AUC (0-infinity) and elimination half-life. The β-CDNSc reportedly eliminated the common side effects observed after intravenous injection of amiodarone. The data regarding the half-life of amiodarone was highly variable (17.646 h+/−14.04 h (control) and 36.264 h+/−32.332 h).
International Publication No. 91/04026 to Palmer et al. discloses liquid formulations containing amiodarone with α-cyclodextrin, β-cyclodextrin, λ-cyclodextrin, δ-cyclodextrin, dimethyl-β-cyclodextrin, or amino-cyclodextrin. An in vivo pig study was conducted wherein pigs were orally administered the amiodarone and amino-cyclodextrin.
The safety of cyclodextrins is often compared by way of in-vitro hemolysis studies. As depicted in FIG. 1 (Thompson, D. O., Critical Reviews in Therapeutic Drug Carrier Systems, (1997), 14(1), 1-104), the hemolytic behavior of the CAPTISOL® cyclodextrin is compared to the same for the parent β-cyclodextrin, the commercially available hydroxypropyl derivatives, ENCAPSIN™ (degree of substitution˜4; HP4-β-CD) and MOLECUSOL™ (degree of substitution˜8; HP8-β-CD), and two other sulfobutyl ether derivatives, SBE1-β-CD and SBE4-β-CD. Unlike the other cyclodextrin derivatives, SAE-CD derivatives, in particular those such as the CAPTISOL® cyclodextrin (degree of substitution˜7; SBE7-β-CD) and SBE4-β-CD (degree of substitution˜4), show essentially no hemolytic behavior in concentrations typically used to solubilize pharmaceutical formulations. These SAE-CDs exhibit substantially lower membrane damaging potential than the commercially available hydroxypropyl derivatives.
Sulfated cyclodextrin derivatives have also been prepared and their effects on blood clotting time evaluated. Sulfated cyclodextrins were found to interfere significantly with blood clotting time, especially when compared to the sulfoalkyl ether cyclodextrins (Thompson, D. O., Critical Reviews in Therapeutic Drug Carrier Systems, (1997), 14(1), 1-104).
Methylated cyclodextrins have been prepared and their hemolytic effect on human erythrocytes has been evaluated. These cyclodextrins were found to cause moderate to severe hemolysis (Jodal et al., Proc. 4th Int. Symp. Cyclodextrins, (1988), 421-425; Yoshida et al., Int. J. Pharm., (1988), 46(3), 217-222).
By virtue of their respective functional groups, derivatized cyclodextrins can differ in terms of their state of ionization when present in solutions at different pH values. The functional group of carboxy-β-cyclodextrins, (e.g. succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-carboxypropyl)-β-cyclodextrin) typically has a pKa of approximately 3-5. Thus, carboxy cyclodextrins typically are charged in solutions at pH 3.5-14. As the pH decreases below the pKa of the functional groups of carboxy-β-cyclodextrin, the overall negative charge of the cyclodextrin decreases. The ionization state for neutral cyclodextrins such as HPCD does not change over the pharmaceutically relevant pH range. However, the sulfoalkyl ether cyclodextrin (SAE-CD), unlike most cyclodextrins, has a pKa of less than one, meaning that in solution, the SAE-CD remains fully ionized throughout the pH range usuable for drug formulation (pH 1-14). Although no literature is available regarding the change in ionization versus solution pH for the sulfate derivatized cyclodextrin, it is assumed that the sulfate derivatized cyclodextrins are also fully ionized over the pH range of 1-14.
The disclosures described above do not describe whether amiodarone is in an ionized state when administered or whether its carrier cyclodextrin is ionized upon administration.
Accordingly, of the different cyclodextrins mentioned above, only the sulfoalkyl ether cyclodextrins and the hydroxypropyl cyclodextrins have demonstrated sufficient safety to be suitable for parenteral administration.
None of the known art has been able to overcome the disadvantages inherent in the present CORDARONE® formulation and a need remains for improved parenteral formulations of amiodarone. A need remains for improved formulations that are readily dilutable from a concentrated solution while maintaining clarity, can be administered at a physiologically acceptable or relevant pH, remain chemically stable under a variety of storage conditions, are easier to handle and administer, and that reduce the severity or occurrence of the side effects, such as hypotension, bradycardia, hemolysis, and phlebitis, of presently marketed formulations of amiodarone. Additionally, an improved parenteral formulation that eliminates side effects associated with a surfactant or organic solvent is needed. None of the art discloses or suggests the invention as claimed herein.